1. Field of the Invention
The present invention relates to novel anti-arrhythmic compositions and methods of treating cardiac arrhythmia wherein the active anti-arrhythmic agent is one of several classes of polyamines and certain derivatives thereof.
2. Description of the Prior Art
Cardiac arrhythmias are disorders involving the electrical impulse generating system of the heart. The disorders include premature contractions (extrasystoles) originating in abnormal foci in atria or ventricles, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular fibrillation and ventricular tachycardia [Goodman et al, eds., The Pharmacological Basis of Therapeutics, Sixth Edition, New York, MacMillan Publishing Co., pages 761-767 (1980)]. More particularly, cardiac arrhythmia is a disorder of rate, rhythm or conduction of electrical impulses within the heart. It is often associated with coronary artery diseases, e.g., myocardial infarction and atherosclerotic heart disease. Arrhythmia can eventually cause a decrease of mechanical efficiency of the heart, reducing cardiac output. As a result, arrhythmia can have life-threatening effects that require immediate intervention.
Anti-arrhythmic drugs are commonly divided into four classes according to their electro-physiological mode of action. See Edvardsson, Current Therapeutic Research, Vol. 28, No. 1 Supplement, pages 113S-118S (July 1980); and Keefe et al, Drugs, Vol. 22, pages 363-400 (1981) for background information of classification first proposed by Vaughn-Williams [Classification of Anti-Arrhythmic Drugs in Symposium of Cardiac Arrhythmias, pages 449-472, Sandoe et al, (eds.) A. B. Astra, Soederlalje, Sweden (1970)].
The classification of anti-arrhythmic drugs is as follows:
I. Local anesthetic effect PA1 II. Beta-receptor blockade PA1 III. Prolongation of action potential duration PA1 IV. Calcium antagonism. PA1 R and R' may be the same or different and are H, alkyl, fluoroalkyl or aralkyl having from 1 to 12 carbon atoms; PA1 R.sub.1 -R.sub.4 may be the same or different and are H, R or R'; PA1 m and n may be the same or different and are integers from 2 to 10, inclusive; and PA1 x, y and z may be the same or different and are integers from 0 to 8, inclusive;
Class I agents usually have little or no effect on action potential duration and exert local anesthetic activity directly at cardiac cell membrane. Class II agents show little or no effect on the action potential and exert their effects through competitive inhibition of beta-adrenergic receptor sites, thereby reducing sympathetic excitation of the heart. Class III agents are characterized by their ability to lengthen the action potential duration, thereby preventing or ameliorating arrhythmias. Class IV agents are those which have an anti-arrhythmic effect due to their actions as calcium antagonists.